Abstract Background Worldwide, sentinel node biopsy (SNB) is the recommended staging procedure for stage I/II melanoma. Most melanoma guidelines recommend re-excision plus SNB as soon as possible ...after primary excision. To date, there is no evidence to support this timeframe. Aim: To determine melanoma specific survival (MSS) for time intervals between excisional biopsy and SNB in SNB positive patients. Methods Between 1993-2008, 1 080 patients were diagnosed with a positive SNB in nine Melanoma Group centers. We selected 1 015 patients (94%) with known excisional biopsy date. Time interval was calculated from primary excision until SNB. Kaplan-Meier estimated MSS was calculated for different cutoff values. Multivariable analysis was performed to correct for known prognostic factors. Results Median age was 51 years (Inter Quartile Range (IQR) 40-62 years), 535 (53%) were men, 603 (59%) primary tumors were located on extremities. Median Breslow thickness was 3.00mm (IQR 1.90-4.80mm), 442 (44%) were ulcerated. Median follow-up was 36 months (IQR 20-62 months). Median time interval was 47 days (IQR 32-63 days). Median Breslow thickness was equal for both <47 days and ≥47 days interval: 3.00mm (1.90-5.00mm) vs 3.00mm (1.90-4.43mm) (p=0.402). Sentinel node tumor burden was significantly higher in patients operated ≥47 days (p=0.005). Univariate survival was not significantly different for median time interval. Multivariable analysis confirmed that time interval was no independent prognostic factor for MSS. Conclusions Time interval from primary melanoma excision until SNB was no prognostic factor for MSS in this SNB positive cohort. This information can be used to counsel patients.
Objectives The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene ( LPA ) on vascular diseases with different atherosclerotic and thrombotic components. ...Background It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. Methods The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST Trial of Org 10172 in Acute Stroke Treatment subtypes) (effective sample size ne = 9,396); peripheral arterial disease ( ne = 5,215); abdominal aortic aneurysm ( ne = 4,572); venous thromboembolism ( ne = 4,607); intracranial aneurysm ( ne = 1,328); CAD ( ne = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). Results LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio OR: 1.27; p = 6.7 × 10–4 ), peripheral artery disease (OR: 1.47; p = 2.9 × 10–14 ), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10–5 ), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10–12 ). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (–1.58 years/allele; p = 8.2 × 10–8 ) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). Conclusions LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.
The pathologist workforce in the United States is a topic of interest to the health-care community as a whole and to institutions responsible for the training of new pathologists in particular. ...Although a pathologist shortage has been projected, there has been a pervasive belief by medical students and their advisors that there are “no jobs in pathology.” In 2013 and again in 2017, the Program Directors Section of the Association of Pathology Chairs conducted surveys asking pathology residency directors to report the employment status of each of their residents graduating in the previous 5 years. The 2013 Program Directors Section survey indicated that 92% of those graduating in 2010 had obtained employment within 3 years, and 94% of residents graduating in 2008 obtained employment within 5 years. The 2017 survey indicated that 96% of those graduating in 2014 had obtained employment in 3 years, and 97% of residents graduating in 2012 obtained positions within 5 years. These findings are consistent with residents doing 1 or 2 years of fellowship before obtaining employment. Stratification of the data by regions of the country or by the size of the residency programs does not show large differences. The data also indicate a high percentage of employment for graduates of pathology residency programs and a stable job market over the years covered by the surveys.
Background A disintegrin and metalloprotease 33 (ADAM33) polymorphism is strongly associated with asthma and bronchial hyperresponsiveness. Although considered to be a mesenchymal cell–specific gene, ...recent reports have suggested epithelial expression of ADAM33 in patients with severe asthma. Objectives Because dysregulated expression of ADAM33 can contribute to disease pathogenesis, we characterized the mechanism or mechanisms that control its transcription and investigated ADAM33 expression in bronchial biopsy specimens and brushings from healthy and asthmatic subjects. Methods The ADAM33 promoter and CpG island methylation were analyzed by using bioinformatics, luciferase reporters, and bisulfite sequencing of genomic DNA. Epithelial-mesenchymal transition was induced by using TGF-β1. ADAM33 mRNA was scrutinized in bronchial biopsy specimens and brushings by using reverse transcriptase–quantitative polymerase chain reaction, melt-curve analysis, and direct sequencing. Results The predicted ADAM33 promoter (−550 to +87) had promoter transcriptional activity. Bisulfite sequencing showed that the predicted promoter CpG island (−362 to +80) was hypermethylated in epithelial cells but hypomethylated in ADAM33-expressing fibroblasts. Treatment of epithelial cells with 5-aza-deoxycytidine caused demethylation of the CpG island and induced ADAM33 expression. In contrast, phenotypic transformation of epithelial cells through a TGF-β–induced epithelial-mesenchymal transition was insufficient to induce ADAM33 expression. ADAM33 mRNA was confirmed in bronchial biopsy specimens, but no validated signal was detected in bronchial brushings from healthy or asthmatic subjects. Conclusion The ADAM33 gene contains a regulatory CpG island within its promoter, the methylation status of which tightly controls its expression in a cell type–specific manner. ADAM33 repression is a stable feature of airway epithelial cells, irrespective of disease.
Background Asthma pathogenesis involves gene and environmental interactions. A disintegrin and metalloprotease 33 (ADAM33)/Adam33 is a susceptibility gene for asthma and bronchial hyperresponsiveness ...in human beings and mice. ADAM33 is almost exclusively expressed in mesenchymal cells, including mesenchymal progenitors in developing lungs. Objective Because maternal allergy is a risk factor for asthma, we hypothesized that an allergic environment affects ADAM33/Adam33 expression during human and mouse lung development. Methods Human embryonic/fetal lung (HEL) tissues were collected from first-trimester terminations of pregnancy. These were processed immediately or used for explant culture ± IL-13. MF1 mice or ovalbumin-sensitized A/J mice ( Bronchial hyperresponsivness (Bhr)1/Adam33 locus–positive) were time-mated and challenged with ovalbumin (A/J mice only) during pregnancy. Lungs were harvested at different times during gestation and post partum. ADAM33/Adam33 expression was analyzed by using reverse transcriptase quantitative polymerase chain reaction and Western blotting. Results ADAM33 mRNA was detectable in HELs in the pseudoglandular stage of development and showed a significant increase from 7 to 9 weeks postconception. IL-13 significantly suppressed ADAM33 mRNA in HEL explants. In developing murine lungs, Adam33 mRNA and protein expression increased significantly in the early pseudoglandular stage and showed another large increase post partum . In A/J mice, maternal allergy significantly suppressed Adam33 mRNA in lungs of newborn pups, whereas processed Adam33 protein increased and several smaller isoforms were detected. Conclusion Adam33 /Adam33 shows 2 significant increments in expression during lung morphogenesis, suggesting important developmental regulation. The ability of maternal allergy or exogenous IL-13 to suppress Adam33 / ADAM33 mRNA but enhance Adam33 processing suggests a gene-environment interaction that may be relevant for asthma pathogenesis.
Professionalism and physician well-being are important topics in academic medicine. Lapses in professional judgment may lead to disciplinary action and put patient’s health at risk. Within medical ...education, students and trainees are exposed to professionalism in the institution’s formal curriculum and hidden curriculum. Development of professionalism starts early in medical school. Trainees entering graduate medical education already have developed professional behavior. As a learned behavior, development of professional behavior is modifiable. In addition to role modeling by faculty, other modalities are needed. Use of case vignettes based on real-life issues encountered in trainee and faculty behavior can serve as a basis for continued development of professionalism in trainees. Based on the experience of program directors and pathology educators, case vignettes were developed in the domains of service, research, and education and subdivided into the areas of duty, integrity, and respect. General and specific questions pertaining to each case were generated to reinforce model behavior and overcome professionalism issues encountered in the hidden curriculum. To address physician burnout, cases were generated to provide trainees with the skills to deal with burnout and promote well-being.
Background Outcomes for patients undergoing intervention for restenosis after prior ipsilateral carotid endarterectomy (CEA) in the era of carotid angioplasty and stenting (CAS) are unclear. We ...compared perioperative results and durability of CAS vs CEA in patients with symptomatic or asymptomatic restenosis after prior CEA and investigated the risk of reintervention compared with primary procedures. Methods Patients undergoing CAS and CEA for restenosis between January 2003 and March 2012 were identified within the Vascular Study Group of New England (VSGNE) database. End points included any stroke, death or myocardial infarction (MI) within 30 days, cranial nerve injury at discharge, and restenosis ≥70% at 1-year follow-up. Multivariable logistic regression was done to identify whether prior ipsilateral CEA was an independent predictor for adverse outcome. Results Out of 9305 CEA procedures, 212 patients (2.3%) underwent redo CEA (36% symptomatic). Of 663 CAS procedures, 220 patients (33%) underwent CAS after prior ipsilateral CEA (31% symptomatic). Demographics of patients undergoing redo CEA were comparable to patients undergoing CAS after prior CEA. Stroke/death/MI rates were statistically similar between redo CEA vs CAS after prior CEA in both asymptomatic (4.4% vs 3.3%; P = .8) and symptomatic patients (6.6% vs 5.8%; P = 1.0). No significant difference in restenosis ≥70% was identified between redo CEA and CAS after prior CEA (5.2% vs 3.0%; P = .5). Redo CEA vs primary CEA had increased stroke/death/MI rate in both symptomatic (6.6% vs 2.3%; P = .05) and asymptomatic patients 4.4% vs 1.7%; P = .03). Prior ipsilateral CEA was an independent predictor for stroke/death/MI among all patients undergoing CEA (odds ratio, 2.1; 95% confidence interval, 1.3-3.5). No difference in cranial nerve injury was identified between redo CEA and primary CEA (5.2% vs 4.7%; P = .8). Conclusions In the VSGNE, CEA and CAS showed statistically equivalent outcomes in asymptomatic and symptomatic patients treated for restenosis after prior ipsilateral CEA. However, regardless of symptom status, the risk of reintervention was increased compared with patients undergoing primary CEA.
To investigate whether an artificial intelligence (AI)–based model can predict tumor invasiveness in patients with multifocal lung adenocarcinoma (MFLA).
Patients with MFLA who underwent surgical ...resection were enrolled to a prospective registry trial (NCT01946100). Each identified nodule underwent retrospective computer-aided nodule assessment and risk yield (CANARY)–based AI to determine a quantitative degree of invasiveness. Data regarding age, sex, medical and surgical management, and survival were collected and analyzed. Pathologic review was performed by a pulmonary pathologist with comprehensive histologic subtyping.
From January 1, 2013, through December 31, 2018, 68 patients with MFLA underwent at least 1 surgical resection. Five-year survival for the cohort was 91%, and 10-year survival was 73.6%. No significant differences in survival were observed when separated by sex, number, or size of the nodules. A 10-year survival trend was seen when comparing patients with unilateral (100% survival) vs bilateral disease (66%). Retrospective CANARY-based AI analysis demonstrated that the majority of the nodules present at the time of diagnosis (229/302; 75.8%) were classified good, with an average score of 0.19, suggesting indolent clinical behavior and noninvasive pathology. However, AI-CANARY scores of the surgically removed nodules were significantly higher compared with those of the nonresected nodules (P=.001).
The long-term survival for patients with N0, M0 MFLA who have undergone surgical resection may approach those of stage I non–small cell lung cancer. CANARY-based AI has the potential to stratify individual nodules to help guide surgical intervention versus observation of nodules.
clinicaltrials.gov Identifier: NCT01946100
Competency-based medical education has evolved over the past decades to include the Accreditation Council for Graduate Medical Education Accreditation System of resident evaluation based on the ...Milestones project. Entrustable professional activities represent another means to determine learner proficiency and evaluate educational outcomes in the workplace and training environment. The objective of this project was to develop entrustable professional activities for pathology graduate medical education encompassing primary anatomic and clinical pathology residency training. The Graduate Medical Education Committee of the College of American Pathologists met over the course of 2 years to identify and define entrustable professional activities for pathology graduate medical education. Nineteen entrustable professional activities were developed, including 7 for anatomic pathology, 4 for clinical pathology, and 8 that apply to both disciplines with 5 of these concerning laboratory management. The content defined for each entrustable professional activity includes the entrustable professional activity title, a description of the knowledge and skills required for competent performance, mapping to relevant Accreditation Council for Graduate Medical Education Milestone subcompetencies, and general assessment methods. Many critical activities that define the practice of pathology fit well within the entrustable professional activity model. The entrustable professional activities outlined by the Graduate Medical Education Committee are meant to provide an initial framework for the development of entrustable professional activity–related assessment and curricular tools for pathology residency training.
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